Pacritinib Combined with Sirolimus and Low-Dose Tacrolimus for GVHD Prevention after Allogeneic Hematopoietic Cell Transplantation: Preclinical and Phase I Trial Results

Clin Cancer Res. 2021 May 15;27(10):2712-2722. doi: 10.1158/1078-0432.CCR-20-4725. Epub 2021 Mar 22.

Abstract

Purpose: In this first-in-human, phase I, GVHD prevention trial (NCT02891603), we combine pacritinib (PAC), a JAK2 inhibitor, with sirolimus to concurrently reduce T-cell costimulation via mTOR and IL6 activity. We evaluate the safety of pacritinib when administered with sirolimus plus low-dose tacrolimus (PAC/SIR/TAC) after allogeneic hematopoietic cell transplantation.

Patients and methods: The preclinical efficacy and immune modulation of PAC/SIR were investigated in xenogeneic GVHD. Our phase I trial followed a 3+3 dose-escalation design, including dose level 1 (pacritinib 100 mg daily), level 2 (pacritinib 100 mg twice daily), and level 3 (pacritinib 200 mg twice daily). The primary endpoint was to identify the lowest biologically active and safe dose of pacritinib with SIR/TAC (n = 12). Acute GVHD was scored through day +100. Allografts included 8/8 HLA-matched related or unrelated donor peripheral blood stem cells.

Results: In mice, we show that dual JAK2/mTOR inhibition significantly reduces xenogeneic GVHD and increases peripheral regulatory T cell (Treg) potency as well as Treg induction from conventional CD4+ T cells. Pacritinib 100 mg twice a day was identified as the minimum biologically active and safe dose for further study. JAK2/mTOR inhibition suppresses pathogenic Th1 and Th17 cells, spares Tregs and antileukemia effector cells, and exhibits preliminary activity in preventing GVHD. PAC/SIR/TAC preserves donor cytomegalovirus (CMV) immunity and permits timely engraftment without cytopenias.

Conclusions: We demonstrate that PAC/SIR/TAC is safe and preliminarily limits acute GVHD, preserves donor CMV immunity, and permits timely engraftment. The efficacy of PAC/SIR/TAC will be tested in our ongoing phase II GVHD prevention trial.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Aurora Kinase A / metabolism
  • Bridged-Ring Compounds / administration & dosage*
  • Clinical Trials as Topic
  • Disease Management
  • Drug Evaluation, Preclinical
  • Graft vs Host Disease / diagnosis
  • Graft vs Host Disease / etiology*
  • Graft vs Host Disease / prevention & control*
  • Hematopoietic Stem Cell Transplantation / adverse effects*
  • Hematopoietic Stem Cell Transplantation / methods
  • Histocompatibility Testing
  • Humans
  • Immunophenotyping
  • Immunosuppressive Agents / administration & dosage*
  • Janus Kinase 2 / metabolism
  • Janus Kinase Inhibitors / administration & dosage*
  • Killer Cells, Natural / immunology
  • Killer Cells, Natural / metabolism
  • Mice
  • Pyrimidines / administration & dosage*
  • STAT3 Transcription Factor / metabolism
  • Severity of Illness Index
  • Signal Transduction
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • TOR Serine-Threonine Kinases / metabolism
  • Tacrolimus / administration & dosage*
  • Tissue Donors
  • Transplantation, Homologous

Substances

  • 11-(2-pyrrolidin-1-ylethoxy)-14,19-dioxa-5,7,26-triazatetracyclo(19.3.1.1(2,6).1(8,12))heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene
  • Bridged-Ring Compounds
  • Immunosuppressive Agents
  • Janus Kinase Inhibitors
  • Pyrimidines
  • STAT3 Transcription Factor
  • Janus Kinase 2
  • Aurora Kinase A
  • TOR Serine-Threonine Kinases
  • Tacrolimus

Associated data

  • ClinicalTrials.gov/NCT02891603